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ChemMaps talk at EPA

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The need for navigating the chemical space has become more important due to the increasing size and diversity of chemical biological databases (e.g., Chemspider, DrugBank, ChEMBL, Toxcast). To do so, modelers typically rely on projection techniques applied to series of quantitative molecular descriptors directly computed from two-dimensional chemical structures. However, the multiple cheminformatics steps required to compute and visualize a chemical space are technical, necessitate coding skills, and thus represent a real obstacle for non-specialists. Inspired by the popular Google Maps application, we developed the ChemMaps.com webserver to easily navigate chemical spaces. The first version of ChemMaps was developed to browse and visualize the space of 2,000 FDA-approved drugs and over 6,000 drug candidates. Each compound was initially characterized using a large set of molecular descriptors including 1D-2D RDKIT descriptors and 3D PADEL descriptors (238 1D-2D and 44 3D after removing correlated descriptors). Principal Component Analysis was used to project compounds in three-dimensional space, where compounds’ coordinates in the first two dimensions were calculated using 1D-2D descriptors, and the third dimension (Z axis) was determined using 3D descriptors only. To optimize the representation of the space and the interactive, user-friendly navigation experience, we developed the ChemMaps.com webserver using modern 3D-optimized web technologies such as HTML5, JavaScript, and CGI. The chemical coverage is now being expanded to include environmental chemical space based on the U.S. EPA TSCA inventory, as well as toxicological categorizations based on curated animal study data and predictive high-throughput screening signatures. Users accessing ChemMaps.com can immediately explore the entire compound library using a responsive, mouse-based, easy-to-use navigation tool. Since all information and coordinates are pre-computed, the browsing is instantaneous and does not require computational skills. Similar to searching Google Maps for a specific address, users can search the ChemMaps via a dedicated search bar (e.g., name, indications, pharmacological class, toxicity values) and visualize the space with options to zoom in on chemical “neighborhoods”. Additional browsing, searching, and exporting options are underway, including tools to support read-across and chemical risk assessment.

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ChemMaps talk at EPA

  1. 1. Alexandre Borrel, PhD Postdoctoral Research Fellow, National Institute of Environment Health Sciences, RTP, North Carolina, USA Exploring chemical space using ChemMaps.com @AlBorrel0000-0001-6499-4540
  2. 2. 5/02/2018 2 Introduction More than 1.1060 accessible molecules 1,2,3 (1) Hann, M.M., and Oprea, T.I. (2004). Curr. Opin. Chem. Biol. 8: 255–263. (2) Ursu, O., Rayan, A., Goldblum, A., and Oprea, T.I. (2011). Rev. Comput. Mol. Sci. 1: 760–781. (3) Drew, K. L. M., Baiman, H., Khwaounjoo, P., Yu, B., & Reynisson, J. (2012). Journal of Pharmacy and Pharmacology, 64(4), 490–495.
  3. 3. 5/02/2018 3 Introduction (1) Hann, M.M., and Oprea, T.I. (2004). Curr. Opin. Chem. Biol. 8: 255–263. (2) Ursu, O., Rayan, A., Goldblum, A., and Oprea, T.I. (2011). Rev. Comput. Mol. Sci. 1: 760–781. (3) Drew, K. L. M., Baiman, H., Khwaounjoo, P., Yu, B., & Reynisson, J. (2012). Journal of Pharmacy and Pharmacology, 64(4), 490–495. More than 1.1060 accessible molecules 1,2,3
  4. 4. 5/02/2018 4 Chemical space Chemical space: “…Chemical space’ is a term often used in place of ‘multi- dimensional descriptor space’: it is a region defined by a particular choice of descriptors…” Dobson CM (2004) Nature 432:824–828
  5. 5. 5/02/2018 5 Lipinski C, Hopkins A (2004) Nature 432:855–861. Chemical space
  6. 6. 5/02/2018 6 Chemical space
  7. 7. 5/02/2018 7 Chemical space Locate chemical of interest
  8. 8. 5/02/2018 8 Chemical space Locate chemical of interest Optimization, define analogue, replacement, ….
  9. 9. 5/02/2018 9 Chemical space Investigate ADME-Tox properties Locate chemical of interest Optimization, define analogue, replacement, ….
  10. 10. 5/02/2018 10 Chemical space Drug repurposing Locate chemical of interest Optimization, define analogue, replacement, …. Investigate ADME-Tox properties
  11. 11. 5/02/2018 11 Chemical space Define, visualize domains Locate chemical of interest Optimization, define analogue, replacement, …. Investigate ADME-Tox properties Drug repurposing
  12. 12. 5/02/2018 12 Chemical space Investigate new area
  13. 13. 5/02/2018 13 Efficient tool of navigation Chemical space
  14. 14. 5/02/2018 14 Google Maps
  15. 15. 5/02/2018 15 Google Maps approach • Interactive • Easy to use • Informative • Responsive • …. Chemical space
  16. 16. 5/02/2018 16 DrugMap: compounds ~8,000 drug entries (release 12-2017): • ~2,500 FDA-approved small molecule drugs • Over 5,000 experimental drugs. https://www.drugbank.ca/
  17. 17. 5/02/2018 17 DrugMap: compounds MolVS (RDkit): - SMILES standardization, normalize - Remove salts - Remove hydrogen - Remove fragments (mixture) 8,752 SMILES MolVS: https://molvs.readthedocs.io/en/latest/ Fourches,D. et al. (2016). J. Chem. Inf. Model., 56, 1243–1252. 8,551 canonical SMILES
  18. 18. 5/02/2018 18 DrugMap: compounds MolVS (RDkit): - SMILES standardization, normalize - Remove salts - Remove hydrogen - Remove fragments (mixture) 8,752 SMILES 8,551 canonical SMILES C[S@@](=O)CC[C@H](N)C(O)=O DB02235 C[S+]([O-])CCC(N)C(=O)O DB02165 [Zn2+] …. MolVS: https://molvs.readthedocs.io/en/latest/ Fourches,D. et al. (2016). J. Chem. Inf. Model., 56, 1243–1252.
  19. 19. 5/02/2018 19 DrugMap: descriptors space https://www.drugbank.ca/ RDkit: http://www.rdkit.org/ 1D descriptors: chemical formula 2D descriptors: connectivity C23H34O5 • Molecular weight • Count of atoms • … • Pharmacophore based • … 1D/2D RDKit descriptors (648)
  20. 20. 5/02/2018 20 DrugMap: 3D generation RDkit: http://www.rdkit.org/ https://www.schrodinger.com/ligprep Riniker, S.; Landrum, G. A. J. Chem. Inf. Comp. Sci. 55:2562-74 (2015) 3D generations • Ligprep (Schrödinger suite) • Riniker and Laundrum (RDKit) SMILES SDF
  21. 21. 5/02/2018 21 DrugMap: 3D descriptors Cao,D.-S. et al. (2013) J. Chem. Inf. Model., 53, 3086–3096 3D descriptors: spatial coordinates • Volume • Surface • Charge distribution • … 3D PyDPI descriptors (420)
  22. 22. 5/02/2018 22 DrugMap: descriptors space Samples (Compounds) Variables (descriptors) X1 X2 ... X1068 1 X1,1 X1,2 ... X1,1068 2 X2,1 X2,2 ... X2,1068 ... ... ... ... ... 8550 X8550,1 X8550, 2 ... X8550,1068
  23. 23. 5/02/2018 23 DrugMap: descriptors space Samples (Compounds) Variables (descriptors) X1 X2 ... X1068 1 X1,1 X1,2 ... X1,1068 2 X2,1 X2,2 ... X2,1068 ... ... ... ... ... 8550 X8550,1 X8550, 2 ... X8850,1068 Descriptor selection: • Remove null variance • Pairwise Person’s correlation coefficient < 0.9
  24. 24. 5/02/2018 24 DrugMap: descriptors space Samples (Compounds) Variables (descriptors) X1 X2 ... X238 1 X1,1 X1,2 ... X1, 238 2 X2,1 X2,2 ... X2, 238 ... ... ... ... ... 8550 X8550,1 X8550, 2 ... X8550,238 116 1D/2D descriptors 122 3D descriptors
  25. 25. 5/02/2018 25 PC1 = 14%; PC2=9%; PC3 = 26% • Sufficient coverage of variance • Understandable z = 70 3D descriptors x, y = 116 1D-2D descriptors Multiple PCA DrugMap: descriptors space
  26. 26. www.chemmaps.com
  27. 27. National Institutes of Health U.S. Department of Health and Human Services29 Environmental Chemical Space ~48,000 chemicals with 3D descriptors Informed by regulatory lists*: • Endocrine Disruptor Screening Program • Toxic Substances Control Act Inventory • Canadian Domestic Substances List • Swedish Chemicals Agency ~12,000 chemicals with acute systemic toxicity data • Rat oral LD50 values • GHS/EPA classifications *not inclusive https://comptox.epa.gov/dashboard/
  28. 28. National Institutes of Health U.S. Department of Health and Human Services30 Projection z = 78 3D descriptors x, y = 138 1D-2D descriptors Multiple PCA PC1: 13% PC2: 9% PC3: 24% Coverage of variance
  29. 29. National Institutes of Health U.S. Department of Health and Human Services32 Conclusions • Web based tool (three.js) • Easy to use • Publically accessible • Multiple platforms (mobile, tablet) • Including several navigation options (search bar, description panel, …) • Available for drug space and environmental chemical space (beta)
  30. 30. National Institutes of Health U.S. Department of Health and Human Services33 Conclusions • Web based tool (three.js) • Easy to use • Publically accessible • Multiple platforms (mobile, tablet) • Including several navigation options (search bar, description panel, …) • Available for drug space and environmental chemical space (beta) Requirements • WebGL, JavaScript • Firefox >59, Chrome >65, Safari >5 • 1GB on GPU memory (EnvMap)
  31. 31. National Institutes of Health U.S. Department of Health and Human Services34 Future Vision: Navigation
  32. 32. National Institutes of Health U.S. Department of Health and Human Services35 Future VisionFuture Vision: Navigation • Project new chemical lists on map • Add your chemicals/data/model predictions on the map
  33. 33. National Institutes of Health U.S. Department of Health and Human Services36 Future VisionFuture Vision: Navigation • Select and redefine part of the chemical map on the fly • Project new chemical lists on map • Add your chemicals/data/model predictions on the map
  34. 34. National Institutes of Health U.S. Department of Health and Human Services37 Future Vision: Navigation • Select and redefine part of the chemical map on the fly • Compute distances between several chemicals using various metrics • Project new chemical lists on map • Add your chemicals/data/model predictions on the map
  35. 35. National Institutes of Health U.S. Department of Health and Human Services38 Future Vision : Navigation • Select and redefine part of the chemical map on the fly • Compute distances between several chemicals using various metrics • Project new chemical lists on map • Add your chemicals/data/model predictions on the map • Download area and matrix of distance
  36. 36. National Institutes of Health U.S. Department of Health and Human Services39 Future Vision: Environmental Maps
  37. 37. National Institutes of Health U.S. Department of Health and Human Services40 Future Vision: Environmental Maps • Define and project several domains
  38. 38. National Institutes of Health U.S. Department of Health and Human Services41 Future Vision: Environmental Maps • Define and project several domains • Add entire DSSTox Inventory (>700,000 chemicals)
  39. 39. National Institutes of Health U.S. Department of Health and Human Services42 Future Vision: Environmental Maps • Define and project several domains • Add entire DSSTox Inventory (>700,000 chemicals) • Incorporate diverse biological datasets (e.g. ToxRefDB, HTT)
  40. 40. National Institutes of Health U.S. Department of Health and Human Services43 Future Vision: map on the fly • Define new map on the fly • Chemical databases • Precomputed coordinates • Local version
  41. 41. National Institutes of Health U.S. Department of Health and Human Services44 Future Vision: Virtual reality
  42. 42. Fourches’ lab Dr. Denis Fourches NIEHS Dr. Nicole Kleinstreuer Dr. Kamel Mansouri (contractor, Scitovation)
  43. 43. www.chemmaps.com @SpaceChemMaps
  44. 44. National Institutes of Health U.S. Department of Health and Human Services47 EnvMap: projections Principal component analysis 216 descriptors PC1=14%, PC2 = 11%, PC3 = 9% Independent component analysis
  45. 45. 5/02/2018 48 Principal component analysis 186 descriptors PC1=16%, PC2 = 11%, PC3 = 8% Independent component analysis 186 descriptors Multidimensional-scaling 3D 186 descriptors Euclidian distance DrugMap: projections

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